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Cross talk between Wnt/β-catenin and Irf8 in leukemia progression and drug resistance
Progression and disease relapse of chronic myeloid leukemia (CML) depends on leukemia-initiating cells (LIC) that resist treatment. Using mouse genetics and a BCR-ABL model of CML, we observed cross talk between Wnt/β-catenin signaling and the interferon-regulatory factor 8 (Irf8). In normal hematop...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3804946/ https://www.ncbi.nlm.nih.gov/pubmed/24101380 http://dx.doi.org/10.1084/jem.20130706 |
Sumario: | Progression and disease relapse of chronic myeloid leukemia (CML) depends on leukemia-initiating cells (LIC) that resist treatment. Using mouse genetics and a BCR-ABL model of CML, we observed cross talk between Wnt/β-catenin signaling and the interferon-regulatory factor 8 (Irf8). In normal hematopoiesis, activation of β-catenin results in up-regulation of Irf8, which in turn limits oncogenic β-catenin functions. Self-renewal and myeloproliferation become dependent on β-catenin in Irf8-deficient animals that develop a CML-like disease. Combined Irf8 deletion and constitutive β-catenin activation result in progression of CML into fatal blast crisis, elevated leukemic potential of BCR-ABL–induced LICs, and Imatinib resistance. Interestingly, activated β-catenin enhances a preexisting Irf8-deficient gene signature, identifying β-catenin as an amplifier of progression-specific gene regulation in the shift of CML to blast crisis. Collectively, our data uncover Irf8 as a roadblock for β-catenin–driven leukemia and imply both factors as targets in combinatorial therapy. |
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